rs528255772

Positions:

• chr5-128392078-A-G
• chr5-128392078-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000262464.9(FBN2):​c.1543T>C​(p.Ser515Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S515T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN2 ENST00000262464.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25

Genes affected

FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.1543T>C	p.Ser515Pro	missense_variant	11/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.1390T>C	p.Ser464Pro	missense_variant	10/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.1543T>C	p.Ser515Pro	missense_variant	11/65	1	NM_001999.4	ENSP00000262464	P1
FBN2	ENST00000508989.5	c.1444T>C	p.Ser482Pro	missense_variant	10/33	2		ENSP00000425596
FBN2	ENST00000703787.1	n.1250T>C		non_coding_transcript_exon_variant	10/10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;D;D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.57	T;.;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.2	L;.;L;.
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.9	D;.;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.015	D;.;D;D
Sift4G	Uncertain	0.012	.;.;.;D
Polyphen		0.81	P;.;P;D
Vest4		0.71
MutPred		0.64		Gain of glycosylation at T513 (P = 0.1341);.;Gain of glycosylation at T513 (P = 0.1341);.;
MVP		0.80
MPC		0.80
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.45
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-127727771; COSMIC: COSV52535464;